The present invention relates to prosthetic devices, particularly prosthetic devices coated with a biocompatible substance impregnated with pharmacologically active agents released over a period of time to reduce or eliminate restenosis in blood vessels, stimulate bone growth or regeneration of a neoarterial wall.
Prosthetic devices are artificial devices used to replace or strengthen a particular part of the body. Various prosthetic devices are available, such as joint replacement prosthesis, stent prosthesis and vascular graft prosthesis. When implanting a prosthesis, such as a stent prosthesis described in greater detail latter herein, it is desireable that the prosthesis closely assimilate the characteristics of the tissue or bone that the prosthesis is designed to repair or replace. To this end, many attempts have been made to improve biocompatible and mechanical properties of prosthetic devices.
Percutaneous endovascular prosthetic stents were conceived in the late 1970""s as a way to prevent both acute occlusion and late restenosis after catheter intervention, but initial clinical results of coronary stenting in 1987 were plagued by high ( greater than 20%) acute and subacute thrombosis and were restricted to use as xe2x80x9cbailoutxe2x80x9d for threatened or acute vessel closure. In recent years, stent outcomes have improved progressively with better placement techniques and in 1995, an estimated 700,000 stents were implanted world-wide. Recent STRESS (Stent Restenosis Study, 1994) and BENESTENT trials (Belgium-Netherlands Stent, 1995) demonstrated that stenting of native coronary arteries is associated with greater procedural success. The trials demonstrated that fewer acute, adverse events and less angigraphic restenosis and lower rates of 8-months target vessel revasculerization occurred than in conventional balloon angioplasty. Stents are now used as primary treatment and secondary bailout.
Despite their utility, stents have been plagued by two problems, namely, acute occlusion due to thrombosis and persistent occurrence of restenosis. Recent studies show that coronary stenting results in significant platelet, polymorphonuclear leukocyte, and macrophage activation, as well as activation of the coagulation pathway which induce clots despite passivation and/or anti-coagulation treatment of the stent surface. This limitation relates to the surface exposure of adhesion receptors on activated platelets to the foreign surface of the stent, producing the aforementioned thrombogenic activity that must be countered with intense anti-coagulation regimens. Subacute stent thrombosis occurs most frequently during the first few days after implantation and almost always in the first two weeks. Thereafter, neointimal cells including proliferating smooth muscle cells from the vessel wall and endothelial hyperplastic cells encompass the stent surface and ameliate the risk of stent thrombosis.
Notwithstanding the above, vascular stents have proven to be of great therapeutic value in the treatment and prevention of complications relating to percutaneous transminal coronary angioplasty (PTCA). Mechanical problems of the vessel wall, i.e., vesssel dissection, the most frequent cause of acute closure in about 25% of patients leading to acute myocardial infarction associated with PTCA, is virtually eliminated with stents. However, such major acute and chronic adverse events persist in more than 25% of patients. One of the most important causes is the trombogenicity of the stent itself. Despite increased biocompatability curently available, stents have less than hemocompatability and are further limited because of late incidence in virtually all stents of restenosis, potentially fatal late complications from clotting and an aggressive type of in-stent restenosis resistant to therapy. In-stent restenosis is much more difficult to treat than PTCA restenosis, frequently resulting in coronary artery bypass grafting (CABG).
In addition to the morbidity and mortality, stents are more expensive than PTCA and require longer hospitalization in order to provide anticoagulant and antispasm therapy due to the induction of thrombogenicity and spasm by the stent, a foreign object, introduced into the vascular wall. The heavy anticoagulation required can produce major bleeding events and vascular complications, often necessitating surgical intervention.
What is desired is a stent coating of antithrombolic, antispasm agents which will biodegrade over time, eluting drugs into the vessel wall to inhibit these complications and obviating systemic oral or intravenous or intraarterial drug delivery with heightened cost and side effect profile. PGE1 is the ideal antithrombolic agent and antispasmodic agent, which also has antiproliferative effects on the smooth muscle cell (SMC). In addition, PGE1 is very effective in antiplatelet activation and deposition, and produces blocking effects on leukocyte adhesion molecules through the lipoxygenase and leukotriene pathway and blocks macrophage migration and aggregation at the injury site.
Much work has been done to both passivate and/or biologically enhance the surface porperties of stents so as to reduce the need for anticoagulants and the like. For example, Bolz, et al., described a process for coating stents with a semi-conductor (Bolz, A., et al, Coating of Cardiovascular Stents with a Semi-Conductor to Improve Their Hemocompatability, Tex. Heart Inst. Jour. 1996;23:162-6) which provided electrical passivation of the surface charge of stents thereby neutralizing the attraction of coagulating proteins. Other investigations have grafted both active and neutral substances to stents, such as hirudin or neutral collagen, in attempts to ameliate coagulation. (Prietzel, K. et al. Inhibition of Neointimal Proliferation with a Novel Hirudin/Prostacyclin Analog Eluting Stent Coating in an Animal Overstrech Model, Abstract, Circulation, Supplement 1, Vol. 94, No. 8, Oct. 15, 1996, p. 1-260); U.S. Pat. No. 5,342,387, Summers, Artificial Support for a Blood Vessel. These coatings have proven less than successful in ameliating the total problem. Two factors, cellular proliferation within the stent lumen itself and late vessel wall remolding, remain unsolved.
Restenosis within and around the stent is a process of chronic new endothelial and medial cellular growth, and remolding of the vessel after intervention which usually occurs by the third month postintervention. Restenosis is a continuum of extracellular matrix rebuilding after stretching, which continues from the time of PTCA, peaking at three months and unusually terminating after six months. Although percutaneous delivery of stents has been shown to sightly reduce the frequency of restenosis as compared to PTCA, when such lesions do occur within a stent, they have been considered to result from intimal proliferation with smooth muscle cells, the predominate cell type, and are resistant to treatment, since PTCA is generally precluded and rotational atherectomy or CABG usually required. Therefore, it is obvious that stent occlusion is a two-phase problem having an acute phase in which platelet, leukocyte, macrophage aggregation, and thrombosis is the primary concern and a chronic and late-phase problem in which intimal in-stent proliferation and vessel wall remolding is the primary concern. It is, therefore, an object of the instant invention to overcome both acute and chronic concerns with the foregoing invention.
Since most cellular interactions are protein mediated, the prevention or reduction in protein absorption to a stent would serve to prevent cellular attachment and subsequent events that may otherwise render the stent materials biocompatable but in doing so, produce the unwanted adverse effects of not coating the stent. A stent coated with a composition of both biocompatable agents and drug eluting systems such as PGE1 to retard initial harmful vascular cellular and thrombosis mechanisms, while allowing normal subsequent acceptance of the stent by the vessel wall by orderly vascular cell covering with endothelial and medial cells, and compatible treatment for post-PTCA complications would be desirable.
Poly-L-lactic acid (PLLA)/Poly-caprolactone (PCL) blends of aliphatic polyester polymers have proven to be both biodegradable, resorbable and biocompatible. Depending on the ratio of PLLA to PCL, these coatings can provide a benign substrate that provides a microporous structure that can efficiently be impregnated with biologically active microsphere such as liposomes in the range of 20 nm to 1000 nm.
It is therefore an object of the invention to provide a prosthetic device having a PLLA/PCL coating substrate formed thereon and impregnating the coating substrate with biologically active microspheres.
It is a further object of the invention to provide a prosthetic coating whereby the coating substrate is coated with a layer of PGE1-encapsulated liposomes which release PGE1 over an extended period of time.
The present invention provides a prosthesis coated with a biodegradable, resorbable and biocompatible surface coating. The surface coating is impregnated with biologically active microspheres which controllably release a biologically active agent. The biologically active microspheres include encapsulated PGE1 in a water soluble polyethylene glycol mixture, which over a period of time dissolves and releases the PGE1.